EP0418004B1 - Vorbeugendes und therapeutisches Mittel gegen Hepatitis - Google Patents

Vorbeugendes und therapeutisches Mittel gegen Hepatitis Download PDF

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Publication number
EP0418004B1
EP0418004B1 EP90309859A EP90309859A EP0418004B1 EP 0418004 B1 EP0418004 B1 EP 0418004B1 EP 90309859 A EP90309859 A EP 90309859A EP 90309859 A EP90309859 A EP 90309859A EP 0418004 B1 EP0418004 B1 EP 0418004B1
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Prior art keywords
use according
pge1
fat emulsion
oil
compound
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English (en)
French (fr)
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EP0418004A2 (de
EP0418004A3 (en
Inventor
Masahiro C/O Chuo Kenkyusho Of Watanabe
Kazumasa C/O Chuo Kenkyusho Of Yokoyama
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Mitsubishi Tanabe Pharma Corp
Taisho Pharmaceutical Co Ltd
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Green Cross Corp Japan
Taisho Pharmaceutical Co Ltd
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to the use of a fat emulsion containing a compound having prostaglandin E1 activities, more particularly to a preventive and/or therapeutic agent for hepatitis using such a fat emulsion.
  • Fat emulsions of prostaglandin E1 and alkyl ester derivatives thereof are disclosed in EP-A-0097481 and EP-A-0132027 respectively. They provide focus selectivity in providing vasodilative and hypotensive actions.
  • hepatitis Another form of hepatitis, fulminant hepatitis, has developed at a time when acute hepatitis has been receding (rate of development being about 2%). Fulminant hepatitis is caused by hepatic virus etc. and is typified by rapid development of symptoms of hepatic insufficiency. A high percentage of the patients suffering from this disease die from hepatic coma in some to 10 days after development of the symptoms.
  • a fat emulsion containing a compound having prostaglandin E1 (hereinafter referred to as PGE1) activities is not only potent against fulminant hepatitis but also more widely useful for the treatment of many types of hepatitis.
  • the preventive and/or therapeutic agent for use in prevention or therapeutic treatment of hepatitis comprises a fat emulsion containing a compound having PGE1 activities.
  • the invention provides use of a compound having PGE1 activity in the manufacture of a medicament for prevention and/or therapeutic treatment of hepatitis, which medicament is in the form of a fat emulsion of the said compound having PGE1 activity.
  • the invention provides use, in the manufacture of a medicament for prevention and/or therapeutic treatment of hepatitis, of a fat emulsion containing a compound having prostaglandin E1 activities.
  • the compounds having PGE1 activities usable in the present invention include all the pharmaceutically acceptable compounds which have PGE1 activities.
  • PGE1 and its derivatives are typical examples.
  • PGE1 derivatives usable in this invention are those which have PGE1 activities and are suited for use as a pharmaceutical component.
  • the PGE1 derivatives disclosed in US-A-4849451 and EP-A-0 132 027 (JP-A-59 216820) are preferred.
  • PGE1 and its derivatives are those represented by the general formula wherein R denotes hydrogen and an alkyl group having 1 to 30 carbon atoms respectively.
  • the alkyl group in the above general formula may have either a straight chain or branched chain.
  • the number of carbon atoms which it has is 1 to 30, preferably 1 to 15 and more preferably 3 to 10.
  • Examples of such alkyl groups include methyl, ethyl n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl.
  • a fat emulsion containing a compound having PGE1 activities which constitutes the active ingredient for use in the manufacture of a medicament useful as preventive and therapeutic agent for hepatitis according to the present invention, may comprise, for instance, 5 to 50, preferably 10 to 20% (W/V) of a vegetable oil, 1 to 50, preferably 5 to 30 parts by weight of phospholipid for 100 parts by weight of the vegetable oil, a proper quantity of water, and an effective quantity of a compound having PGE1 activities.
  • the fat emulsion may be added, if necessary, with 0.3% (W/V) or less of an emulsifier adjuvant, 5% (W/V) or less of a stabilizer, a polymeric substance as stabilizing adjuvant in an amount of 0.1 to 5, preferably 0.5 to 1 parts by weight to 1 part of the compound having PGE1 activities (i.e. PGE1 or PGE1 derivative), and 0.1 - 10% (W/V) of an isotonizing agent (for example, glycerin and glucose).
  • an isotonizing agent for example, glycerin and glucose
  • the content of the compound having PGE1 activities in the fat emulsion can be properly varied depending on the form of emulsion, the manner of administration, etc., but usually the compound is present in an amount of 0.2 to 100 »g/ml in the emulsion.
  • the vegetable oil to be added to the fat emulsion may be soybean oil, sesame oil, castor oil, cottonseed oil and olive oil, and soybean oil is preferred. It is more preferred to use a highly purified soybean oil, particularly preferably a high-purity soybean oil (purity: 99.9% or above as tri-, di- and mono-glyceride) obtained by further purifying the commonly purified soybean oil by steam distillation or other like means.
  • phospholipid there can be used purified phospholipid such as egg yolk phospholipid and soybean phospholipid, and it can be prepared by a conventional fractionation method using an organic solvent. For instance, crude egg yolk phospholipid is dissolved in a cold n-hexane-acetone mixed solvent, slowly adding acetone thereto with stirring, followed by filtering-out of insolubles, and after repeating this operation once more, the solvent is distilled off to obtain the desired purified phospholipid.
  • the thus obtained phospholipid mainly consists of phosphatidyl choline and phosphatidyl ethanolamine. It also contains other phospholipids such as phosphatidyl inositol, phosphatidyl serine, sphingomyelin and the like in smaller quantities.
  • the emulsifying adjuvant includes fatty acids of 6 to 22, preferably 12 to 20 carbon atoms which are pharmaceutically acceptable. These fatty acids may have either a straight chain or branched chain, but straight-chain stearic acid, oleic acid, linolic acid, palmitic acid, linolenic acid, myristic acid and the like are preferred. It is also possible to use their pharmaceutically acceptable salts such as alkali metal salts (sodium salt, potassium salt, etc.) and alkaline earth metal salts (calcium salt, etc.).
  • the stabilizer includes cholesterols and phosphatidic acid which are pharmaceutically usable, and are used in an amount of 0.5, preferably 0.1% (W/V) and in an amount of 5, preferably 1% (W/V), respectively.
  • the polymeric substance includes albumin, dextran, vinyl polymer, nonionic surfactant, gelatin and hydroxyethyl starch, and preferred types of albumin, vinyl polymers and nonionic surfactants usable as polymeric substance are as follows.
  • Albumin should be of the human origin in consideration of antigenicity.
  • a typical example of a vinyl polymer is polyvinylpyrrolidone.
  • nonionic surfactant there can be used polyalkylene glycol (for example, polyethylene glycol having an average molecular weight of 1,000 to 10,000, preferably 4,000 to 6,000), polyoxalkylene copolymers (for example, polyoxyethylene-polyoxypropylene copolymer having an average molecular weight of 1,000 to 20,000, preferably 6,000 to 10,000), hardened castor oil polyoxyalkylene derivatives [for example, hardened castor oil polyoxyethylene-(40), -(20) and -(100) ether], and castor oil polyoxyalkylene derivatives [for example, castor oil polyoxyethylene-(20), -(40) and -(100) ether].
  • polyalkylene glycol for example, polyethylene glycol having an average molecular weight of 1,000 to 10,000, preferably 4,000 to 6,000
  • polyoxalkylene copolymers for example, polyoxyethylene-polyoxypropylene copolymer having an average molecular weight of 1,000 to 20,000, preferably 6,000 to
  • Glycerin or glucose which may be used as isotonizing agent in this invention is pharmaceutically acceptable.
  • the fat emulsion used in the present invention can be prepared by various methods. For example, it can be produced in the following way.
  • a vegetable oil preferably soybean oil
  • phospholipid preferably phospholipid
  • a compound having PGE1 activities and other additives such as mentioned above are mixed and added with a necessary amount of water.
  • This solution is homogenized by a commonly used homogenizer (such as a pressure-jet type homogenizer or an ultrasonic homogenizer) to prepare an oil-in-water type emulsion, whereby a desired fat emulsion is produced.
  • the thus produced fat emulsion may be further added with a stabilizer, isotonizing agent and other additive(s) if necessary for reasons relating to formulation.
  • the preventive and therapeutic agent for hepatitis used in accordance with this invention for preparing a medicament comprising said fat emulsion is usually administered by intravenous injection, continuous drip infusion, or in other appropriate ways.
  • the agent is generally given at a dose of about 0.1 to 20 »g/kg body weight, preferably 1 to 10 »g/kg body weight, in terms of quantity of active ingredient, in one administration for adults, but the dose may be properly adjusted according to the condition of the patient, the region of application, etc.
  • the medicament prepared using the preventive and therapeutic agent for hepatitis according to the present invention is considered to be particularly effective for the treatment of fulminant hepatitis.
  • it has potenties for various types of hepatitis; it is not only utility against fulminant hepatitis but also effective for the treatment of viral hepatitis, alcoholic hepatitis, drug-induced hepatitis, acute and chronic hepatitis, and useful for the prevention of hepatic insufficiency, hepatocirrhosis and other hepatic diseases.
  • the medicament prepared using the preventive and therapeutic agent for hepatitis according to this invention is capable of retaining its efficacy for a long time in the living body and can produce a sufficient action with a small dose. This effect is more remarkable than the PGE1 cyclodextrin clathrate.
  • the present agent therefore is of extremely high clinical utility for the prevention and therapeutics of heptatitis.
  • This crude emulsion was passed through Manton-Gaulin homogenizer under high pressure, whereby a fat emulsion containing homogenized, extremely fine PGE1 particles could be obtained (this fat emulsion is hereinafter referred to as PGE1-lipo).
  • This emulsion had an average particle diameter of 0.2 to 0.4 »m.
  • a fat emulsion was prepared in the same way as in Example 1 except that 0.15 g of sodium oleate was used in place of 0.15 g of sodium palmitate and 0.15 g of phosphatidic acid.
  • P. acnes which is a Gram-positive anaerobe
  • LPS lipopolysaccharide
  • PGE1-lipo prepared in Example 1 was intravenously injected (tail vein) (at a dose of 0.25 »g/mouse and 0.5 »g/mouse in terms of the quantity of PGE1) to the test mice just before giving LPS, and the rate of survival of the mice after the lapse of 24 hours was examined.
  • cyclodextrin clathrate of PGE1 PGE1-CD
  • PGE1-CD cyclodextrin clathrate of PGE1
  • Table 1 Specimen Rate of survival (%) 10 hrs. after giving LPS 24 hrs. after giving LPS Physiological saline solution (control) 20 10 PGE1-lipo (0.25 »g/animal) 50 30 PGE1-lipo (0.5 »g/animal) 80 60 PGE1-CD (0.5 »g/animal) 40 10 LPS was administered 7 days after giving P. acnes , and each specimen was administered just before giving LPS.
  • Endotoxin is considered to play an important role against a rapid development of symptoms of hepatic insufficiency.
  • Test Example 1 shows, by administering heated-killed P. acnes, monocitosis is induced in the liver. A further administration of endotoxin causes apparent necrosis of the liver, which proceeds to death. The present drug showed very strong life-saving effects against such hepatic insufficiency.
  • hepatic homogenate supernatant fraction (4 mg/ml) treated with sodium 2,4,6-trinitrobenzenesulfonate (TNP) was administered along with an equal amount of Freund complete adjuvant (FCA) subcutaneously to the heels of guinea pigs (body weight: 400-500 g; divided into groups of 10). 2 weeks thereafter, 5 x 106 TNP-treated liver cells were given into the mesentric vein to induce immunological hepatic insufficiency cytotoxic trouble.
  • FCA Freund complete adjuvant
  • Example 2 PGE1-lipo prepared in Example 1 was administered intravenously (0.05 »g/animal, 0.1 »g/animal and 0.2 »g/animal in terms of quantity of PGE1) just before giving the TNP-treated liver cells, and 24 hours thereafter, the effect on rise of serum GOT and GPT was investigated. A physiological saline solution was given to the comparative control group in the similar way. The results are shown in Table 2. GOT of the normal (non-treated) guina pigs was 48 ⁇ 10 (IU/l) and GPT thereof was 45 ⁇ 7 (IU/l).

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Dispersion Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Claims (11)

  1. Verwendung einer Verbindung mit PGE₁-Wirksamkeit zur Herstellung eines Arzneimittels zur Vorbeugung und/oder therapeutischen Behandlung von Hepatitis, wobei das Arzneimittel in Form einer Fettemulsion der Verbindung mit PGE₁-Wirksamkeit vorliegt.
  2. Verwendung gemäß Anspruch 1, wobei die Fettemulsion eine Verbindung mit Prostaglandin-E₁-Wirksamkeiten der allgemeinen Formel
    Figure imgb0003
     in der R ein Wasserstoffatom oder einen Alkylrest mit 1 bis 30 Kohlenstoffatomen bezeichnet, in einer Menge von 0,2 bis 100 »g pro ml der Emulsion, 5 bis 50 % (w/v) eines pflanzlichen Öls, 10 bis 50 % (w/v) Phospholipid auf 100 Gewichtsteile des pflanzlichen Öls und eine geeignete Wassermenge enthält.
  3. Verwendung gemäß Anspruch 2, wobei das pflanzliche Öl Sojabohnenöl, Sesamöl, Rizinusöl, Baumwollsamenöl oder Ölivenöl ist.
  4. Verwendung gemäß Anspruch 3, wobei das pflanzliche Öl Sojabohnenöl ist.
  5. Verwendung gemäß Anspruch 2, 3 oder 4, wobei das Phospholipid Eidotterphospholipid oder Sojabohnenphospholipid ist.
  6. Verwendung gemäß einem der Ansprüche 2 bis 5, wobei die Fettemulsion als emulgierendes Adjuvans 0,3 % (w/v) oder weniger einer Fettsäure mit 6 bis 22 Kohlenstoffatomen oder eines pharmazeutisch verträglichen Salzes davon enthält.
  7. Verwendung gemäß einem der Ansprüche 2 bis 6, wobei die Fettemulsion als Stabilisator 0,5 % (w/v) oder weniger eines Cholesterins oder 5 % (w/v) oder weniger einer Phosphatidsäure enthält.
  8. Verwendung gemäß einem der Ansprüche 2 bis 7, wobei die Fettemulsion als stabilisierendes Adjuvans 0,1 bis 0,5 Gewichtsteile wenigstens einer polymeren Substanz, ausgewählt aus Albumin, Dextran, Vinylpolymeren, nichtionischen Netzmitteln, Gelatine und Hydroxyethylstärke auf 1 Gewichtsteil der Verbindung mit PGE₁-Wirksamkeiten enthält.
  9. Verwendung gemäß einem der Ansprüche 2 bis 8, wobei die Fettemulsion als isotonisierendes Mittel 0,1 bis 10 % (w/v) Glycerin oder Glucose enthält.
  10. Verwendung gemäß einem der vorstehenden Ansprüche zur Vorbeugung und/oder Behandlung fulminanter Hepatitis.
  11. Verwendung einer Fettemulsion, enthaltend eine Verbindung mit Prostaglandin-E₁-Wirksamkeiten, zur Herstellung eines Arzneimittels zur Vorbeugung und/ oder therapeutischen Behandlung von Hepatitis.
EP90309859A 1989-09-11 1990-09-10 Vorbeugendes und therapeutisches Mittel gegen Hepatitis Expired - Lifetime EP0418004B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP235386/89 1989-09-11
JP1235386A JPH03101622A (ja) 1989-09-11 1989-09-11 肝炎予防治療剤

Publications (3)

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EP0418004A2 EP0418004A2 (de) 1991-03-20
EP0418004A3 EP0418004A3 (en) 1991-12-27
EP0418004B1 true EP0418004B1 (de) 1995-08-02

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EP90309859A Expired - Lifetime EP0418004B1 (de) 1989-09-11 1990-09-10 Vorbeugendes und therapeutisches Mittel gegen Hepatitis

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US (1) US5091417A (de)
EP (1) EP0418004B1 (de)
JP (1) JPH03101622A (de)
KR (1) KR910005872A (de)
CA (1) CA2024965A1 (de)
DE (1) DE69021304T2 (de)
DK (1) DK0418004T3 (de)
ES (1) ES2075161T3 (de)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2027814C (en) * 1989-10-20 1996-07-30 Ryuji Ueno Treatment of hepatobiliary disease with 15-keto-prostaglandin compounds
EP0455448B1 (de) * 1990-05-01 1998-12-09 R-Tech Ueno Ltd. Behandlung von Pankreaskrankheit mit 15-keto-Prostaglandin E-Derivaten
US5348764A (en) * 1992-10-06 1994-09-20 Yasuhiro Yokoshima Method for impregnating a lining material with a hardenable resin
US5631287A (en) * 1994-12-22 1997-05-20 Alcon Laboratories, Inc. Storage-stable prostaglandin compositions
US6011062A (en) * 1994-12-22 2000-01-04 Alcon Laboratories, Inc. Storage-stable prostaglandin compositions
EP0857484A4 (de) * 1995-09-13 2000-12-06 Nippon Shinyaku Co Ltd Pge1- enthaltende gefriergetrocknete zubereitung und verfahren zu deren herstellung
ATE237587T1 (de) * 1997-02-10 2003-05-15 Ono Pharmaceutical Co 11,15-o-dialkylprostaglandin-e-derivate, verfahren zu ihrer herstellung und arzneimittel, die diese als aktiven inhaltsstoff enthalten
US6553644B2 (en) 2001-02-09 2003-04-29 International Business Machines Corporation Fixture, carrier ring, and method for processing delicate workpieces
AR059429A1 (es) * 2006-02-09 2008-04-09 Schering Corp Combinaciones que involucran el (los) inhibidor(es) de la protesa hcv y metodos de tratamiento relacionados al (los) mismo (s)

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS58222014A (ja) * 1982-06-18 1983-12-23 Taisho Pharmaceut Co Ltd プロスタグランジンｅ↓１脂肪乳剤
JPS59216820A (ja) * 1983-05-20 1984-12-06 Taisho Pharmaceut Co Ltd プロスタグランジン脂肪乳剤
JPH0818989B2 (ja) * 1984-01-12 1996-02-28 株式会社ミドリ十字 脂肪乳剤中のプロスタグランジンの安定化方法
JPS60181068A (ja) * 1984-02-29 1985-09-14 Teijin Ltd ６−置換プロスタグランジンｅ↓１類およびその製造法

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ES2075161T3 (es) 1995-10-01
JPH03101622A (ja) 1991-04-26
DE69021304D1 (de) 1995-09-07
DK0418004T3 (da) 1995-09-18
KR910005872A (ko) 1991-04-27
DE69021304T2 (de) 1996-01-18
CA2024965A1 (en) 1991-03-12
EP0418004A2 (de) 1991-03-20
US5091417A (en) 1992-02-25
EP0418004A3 (en) 1991-12-27

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